Early detection of pregnancy after IVF and embryo transfer with hyperglycosylated HCG versus Elecsys HCG+ß assay.

RESEARCH QUESTION: Is measurement of hyperglycosylated HCG (hHCG) superior to beta-HCG (HCG+ß) for early pregnancy detection after IVF and embryo transfer? DESIGN: Blood samples were collected on day 4 (+1), 7 (+1) and 11 (+2) after embryo transfer from women aged 18-45 years undergoing first or second fresh or frozen IVF embryo transfer cycles. Biochemical pregnancy was assessed on-site by HCG determination on day 11; clinical pregnancy was assessed by ultrasound on day 21 (+4/-3). Serum hHCG (immunochemiluminometric assay) and HCG+ß (Elecsys® HCG+ß assay) concentrations were measured. Performance of hHCG and HCG+ß for predicting pregnancy was evaluated and cut-offs selected. RESULTS: In total, 155 women were enrolled and underwent IVF and embryo transfer. Area under the curve (AUC) (95% CI) on day 4 was not significantly different for hHCG (AUC 0.88; 95% CI 0.83 to 0.94) and HCG+ß (AUC 0.90; 95% CI 0.84 to 0.95), as was predictive performance on day 7 and 11, with higher AUC estimates compared with day 4. Applying cut-offs derived according to Youden's index on day 4 (hHCG, 100 pg/ml; HCG+ß, 1.30 mIU/ml), both biomarkers demonstrated high negative predictive values for ruling out pregnancy (hHCG, 83.8%; HCG+ß, 82.8%) and high positive predictive values for ruling in pregnancy (hHCG, 89.0%; HCG+ß, 84.9%) on day 21. Diagnostic performance improved from day 4 to day 11. CONCLUSIONS: Predictive performance for early pregnancy post-IVF embryo transfer of day-5 blastocysts was not significantly different for hHCG and HCG+ß; hHCG superiority over HCG+ß was not shown.

Intra- and inter-cycle variability of anti-Müllerian hormone (AMH) levels in healthy women during non-consecutive menstrual cycles: the BICYCLE study.

OBJECTIVES: Determine variability of serum anti-Müllerian hormone (AMH) levels during ovulatory menstrual cycles between different women (inter-participant), between non-consecutive cycles (inter-cycle) and within a single cycle (intra-cycle) in healthy women. METHODS: Eligible participants were women aged 18-40 years with regular ovulatory menstrual cycles. Serum samples were collected every second day during two non-consecutive menstrual cycles. AMH levels were measured in triplicate using the Elecsys® AMH Plus immunoassay (Roche Diagnostics). AMH level variability was evaluated using mixed-effects periodic regression models based on Fourier series. The mesor was calculated to evaluate inter-participant and inter-cycle variability. Inter- and intra-cycle variability was evaluated using peak-to-peak amplitudes. Separation of biological and analytical coefficients of variation (CVs) was determined by analysing two remeasured AMH levels (with and without original AMH levels). RESULTS: A total of 47 women were included in the analysis (42 assessed over two cycles; five one cycle only). CV of unexplained biological variability was 9.61%; analytical variability was 3.46%. Inter-participant variability, given by time-series plots of AMH levels, was greater than inter-cycle variability. Between individual participants, both mesor and peak-to-peak amplitudes proved variable. In addition, for each participant, intra-cycle variability was higher than inter-cycle variability. CONCLUSIONS: Inter-participant and intra-cycle variability of AMH levels were greater than inter-cycle variability. Unexplained biological variability was higher than analytical variability using the Elecsys AMH Plus immunoassay. Understanding variability in AMH levels may aid in understanding differences in availability of antral ovarian follicles during the menstrual cycle, which may be beneficial in designing gonadotropin dosage for assisted reproductive technology.

Gestational Age-Specific Reference Ranges for the sFlt-1/PlGF Immunoassay Ratio in Twin Pregnancies.

OBJECTIVE: Establish reference ranges for the Elecsys® soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) immunoassay ratio in twin pregnancies. METHODS: Data analyzed were from 3 prospective studies: Prediction of Short-Term Outcome in Pregnant Women with Suspected Preeclampsia (PE) (PROGNOSIS), Study of Early-onset PE in Spain (STEPS), and a multicenter case-control study. Median, 5th, and 95th percentiles for sFlt-1, PlGF, and the sFlt-1/PlGF ratios were determined for normal twin pregnancies for 7 gestational windows and compared with the previous data for singleton pregnancies. RESULTS: The reference range analysis included 269 women with normal twin pregnancies. Before 29 weeks' gestation, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios did not differ between twin and singleton pregnancies. From 29 weeks' gestation to delivery, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios were substantially higher in twin versus singleton pregnancies. sFlt-1 values were higher in women with twin pregnancies across all gestational windows. PlGF values were similar or higher in twin versus singleton pregnancies; PlGF concentrations increased from 10 weeks + 0 days to 28 weeks + 6 days' gestation. CONCLUSIONS: Reference ranges for the sFlt-1/PlGF ratio are similar in women with twin and singleton pregnancies until 29 weeks' gestation but appear higher in twin pregnancies thereafter.

Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia.

BACKGROUND: The ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) is elevated in pregnant women before the clinical onset of preeclampsia, but its predictive value in women with suspected preeclampsia is unclear. METHODS: We performed a prospective, multicenter, observational study to derive and validate a ratio of serum sFlt-1 to PlGF that would be predictive of the absence or presence of preeclampsia in the short term in women with singleton pregnancies in whom preeclampsia was suspected (24 weeks 0 days to 36 weeks 6 days of gestation). Primary objectives were to assess whether low sFlt-1:PlGF ratios (at or below a derived cutoff) predict the absence of preeclampsia within 1 week after the first visit and whether high ratios (above the cutoff) predict the presence of preeclampsia within 4 weeks. RESULTS: In the development cohort (500 women), we identified an sFlt-1:PlGF ratio cutoff of 38 as having important predictive value. In a subsequent validation study among an additional 550 women, an sFlt-1:PlGF ratio of 38 or lower had a negative predictive value (i.e., no preeclampsia in the subsequent week) of 99.3% (95% confidence interval [CI], 97.9 to 99.9), with 80.0% sensitivity (95% CI, 51.9 to 95.7) and 78.3% specificity (95% CI, 74.6 to 81.7). The positive predictive value of an sFlt-1:PlGF ratio above 38 for a diagnosis of preeclampsia within 4 weeks was 36.7% (95% CI, 28.4 to 45.7), with 66.2% sensitivity (95% CI, 54.0 to 77.0) and 83.1% specificity (95% CI, 79.4 to 86.3). CONCLUSIONS: An sFlt-1:PlGF ratio of 38 or lower can be used to predict the short-term absence of preeclampsia in women in whom the syndrome is suspected clinically. (Funded by Roche Diagnostics.).

A multicentre evaluation of the Elecsys® anti-Müllerian hormone immunoassay for prediction of antral follicle count.

RESEARCH QUESTION: What concentration of anti-Müllerian hormone (AMH) corresponds to an antral follicle count (AFC) >15 for determination of ovarian reserve? DESIGN: A prospective study conducted at 13 US fertility clinics in women aged 21-44 years who presented for AFC evaluation by transvaginal ultrasound. Serum samples were collected at the time of AFC evaluation (menstrual cycle day 2-4). AMH concentrations were measured by the Elecsys® AMH immunoassay; oestradiol and follicle-stimulating hormone (FSH) concentrations were also measured. The serum AMH cut-off able to detect AFC >15 with high sensitivity was determined (derivation cohort). Clinical performance of the AMH assay at the derived cut-off was evaluated (validation cohort). Receiver operating characteristic (ROC) analyses were also performed. RESULTS: In the derivation cohort (n = 306), an optimal serum AMH cut-off value of 1.77 ng/ml was determined to correspond to AFC >15 with 89.63% sensitivity and 69.01% specificity, using the Elecsys AMH assay. In the validation cohort (n = 856), this 1.77 ng/ml cut-off could identify women with an AFC >15 with a sensitivity of 88.34% and a specificity of 68.29%; corresponding positive predictive and negative predictive values were 75.19% and 84.34%, respectively. ROC analyses demonstrated that AMH performed better than oestradiol or FSH in predicting AFC, with area under the curves of 85.7%, 57.1% and 69.7%, respectively, in the validation cohort. CONCLUSION: The Elecsys AMH immunoassay provides a robust and fully automated method to measure serum AMH levels. Women with AMH values below the cut-off of 1.77 ng/ml are unlikely to have AFC >15.

Elecsys® and Kryptor immunoassays for the measurement of sFlt-1 and PlGF to aid preeclampsia diagnosis: are they comparable?

Background For pregnant women with suspected preeclampsia, the soluble fms-like tyrosine-kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio is a biomarker to aid diagnosis. We performed method comparisons between Elecsys® and Kryptor sFlt-1 and PlGF immunoassays and assessed the diagnostic performance for preeclampsia. Methods Serum samples from a case-control study involving 113 pregnant women with preeclampsia/elevated liver enzymes and low platelet count (HELLP) and 270 controls were analyzed. sFlt-1 and PlGF were measured using Roche Elecsys® and BRAHMS Kryptor sFlt-1/PlGF immunoassays. The sFlt-1/PlGF ratios were calculated, and Passing-Bablok regression/Bland-Altman plots were performed. Gestation-specific cut-offs, ≤33 and ≥85/≥110, were assessed. Results Mean (±2 standard deviation [SD]) differences between the Elecsys® and Kryptor values were: sFlt-1, 173.13 pg/mL (6237.66, -5891.40); PlGF, -102.71 pg/mL (186.06, -391.48); and sFlt-1/PlGF, 151.74 (1085.11, -781.63). The Elecsys® and Kryptor immunoassays showed high correlation: Pearson's correlation coefficients were 0.913 (sFlt-1) and 0.945 (PlGF). Slopes were 1.06 (sFlt-1) and 0.79 (PlGF), resulting in ~20% lower values for Kryptor PlGF. Sensitivities and specificities using the sFlt-1/PlGF ≥85 cut-off for early-onset preeclampsia (20 + 0 to 33 + 6 weeks) were 88.1%/100.0% (Elecsys®) and 90.5%/96.2% (Kryptor), respectively, and using the ≥110 cut-off for late-onset preeclampsia (≥34 + 0 weeks) were 51.3%/96.5% (Elecsys®) and 78.9%/90.1% (Kryptor), respectively. Using Elecsys® and Kryptor sFlt-1/PlGF, 0% and 3.8% of women, respectively, were falsely ruled-in for early-onset, and 3.5% and 9.9%, respectively, for late-onset preeclampsia. Conclusions Despite high correlation between the Elecsys® and Kryptor immunoassays, we observed significant differences between sFlt-1/PlGF and PlGF results. Therefore, sFlt-1/PlGF cut-offs validated for Elecsys® immunoassays are not transferable to Kryptor immunoassays.

The utility of anti-Müllerian hormone in women with chronic kidney disease, on haemodialysis and after kidney transplantation.

Women with renal disease have menstrual and gonadal dysfunction manifesting as hormonal imbalance. Anti-Müllerian hormone (AMH) is a potential measure of ovarian reserve. We examined circulating AMH concentrations in young women with renal failure, determined associations with clinical characteristics, and compared AMH with age-matched healthy individuals. AMH was measured in 77 women: 26 had chronic kidney disease (CKD), 26 were on haemodialysis (HD), and 25 had a kidney transplant. Random AMH levels were highest in women on HD [HD 2.9 (1.1-5.2), CKD 1.6 (0.7-2.2), transplant 1.5 (1.0-4.2) ng/ml]. On multiple linear regression, AMH was 53% higher [95% CI 0.20-0.98, P = 0.002] in women on HD and decreased by 20% per 5-year increase in age (P < 0.001). AMH was 43% lower in women with renal failure compared with 600 age-matched controls [1.7 (0.9-3.8) versus 3.0 (1.9-5.0) ng/ml, P < 0.001]; however, we found no difference in AMH between those on HD and healthy individuals [2.9 (1.1-5.2) versus 3.0 (1.9-5.0) ng/ml]. AMH may be a useful biomarker in female renal patients with non-dialysis dependent renal disease pursuing pregnancy. In contrast, AMH levels are higher in HD but unlikely to reflect ovarian reserve.

Economic assessment of the use of the sFlt-1/PlGF ratio test to predict preeclampsia in Germany.

BACKGROUND: The PRediction of short-term Outcome in preGNant wOmen with Suspected preeclampsIa Study (PROGNOSIS) demonstrated that a soluble fms-like tyrosine kinase 1/placental growth factor (sFlt-1/PlGF) ratio ≤ 38 ruled out the occurrence of preeclampsia in the next week with a negative predictive value of 99.3%; a ratio > 38 indicates an increased risk of developing preeclampsia in the next 4 weeks. We performed an assessment of the economic impact of the sFlt-1/PlGF ratio test for short-term prediction of preeclampsia in Germany. METHODS: We adapted a cost-effectiveness model, which had been developed to estimate the incremental value of adding the sFlt-1/PlGF ratio test with a cut-off ratio of 38 to standard diagnostic procedures for guiding the management of women with suspected preeclampsia in the UK. We used the adapted model to estimate the incremental value of the sFlt-1/PlGF ratio test (cut-off 38) for guiding the management of women with suspected preeclampsia from a German Diagnosis-Related Group (DRG) payer perspective. The economic model estimated costs associated with diagnosis and management of preeclampsia in women managed in either a 'no-test' scenario in which clinical decisions are based on standard diagnostic procedures alone, or a 'test' scenario in which the sFlt-1/PlGF test is used in addition to standard diagnostic procedures. Test characteristics and rates of hospitalization were derived from patient-level data from PROGNOSIS. The main outcome measure from the economic model was the total cost per patient. RESULTS: In the model adapted to the German DRG payer system, introduction of the sFlt-1/PlGF ratio test with a cut-off value of 38 could reduce the proportion of women hospitalized in Germany from 44.6 to 24.0%, resulting in an expected cost saving of €361 per patient. CONCLUSIONS: The sFlt-1/PlGF ratio test is likely to reduce unnecessary hospitalization of women with a low risk of developing preeclampsia, and identify those at high risk to ensure appropriate management. Even within the restrictions of the DRG system in Germany, this results in substantial cost savings for women with suspected preeclampsia.

Multicenter prospective clinical study to evaluate the prediction of short-term outcome in pregnant women with suspected preeclampsia (PROGNOSIS): study protocol.

BACKGROUND: Preeclampsia is defined as new onset of hypertension and proteinuria at gestational week 20 or after. However, use of these measures to predict preeclampsia before its clinical onset is unreliable, and evidence suggests that preeclampsia, eclampsia, or hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome may develop without hypertension or proteinuria being evident. Because of its unpredictability, varying clinical presentation and potential adverse outcomes, pregnant women with suspected preeclampsia require intensive monitoring or hospitalization. Beyond preeclampsia diagnosis, there is a high unmet medical need for more reliable predictive markers for preeclampsia to improve maternal and fetal outcomes and reduce unnecessary hospital admissions. An imbalance of circulating angiogenic and antiangiogenic factors, including raised soluble fms-like tyrosine kinase-1 (sFlt-1) and decreased placental growth factor (PlGF), has been found in women diagnosed with preeclampsia and before clinical onset of the disease. The PRediction of short-term Outcome in preGNant wOmen with Suspected preeclampsIa Study (PROGNOSIS) was designed to investigate the use of the sFlt-1/PlGF ratio in the short-term prediction of preeclampsia. METHODS/DESIGN: This global, multicenter, prospective, double-blind, non-interventional study aims to derive and validate cutoffs for the sFlt-1/PlGF ratio, to rule out (for 1 week) or rule in (within 4 weeks) the occurrence of preeclampsia/eclampsia/HELLP syndrome. Eligible participants are women presenting at 24 to <37 weeks' gestation with clinical suspicion of, but not manifest preeclampsia/eclampsia/HELLP syndrome. Clinical assessments, maternal serum sFlt-1/PlGF sampling and documentation of maternal/neonatal outcomes are performed at regular intervals, using strict diagnostic criteria for preeclampsia-related conditions and outcomes. Serum sFlt-1 and PlGF analysis will be performed using fully automated Elecsys® immunoassays. Investigators and participants will remain blinded to the results. Target recruitment is 1000 participants. Health economic analysis is also planned. DISCUSSION: The results of PROGNOSIS will provide the most comprehensive evidence to date on the accuracy of the sFlt-1/PlGF ratio for short-term prediction of preeclampsia/eclampsia/HELLP syndrome. Adoption of the sFlt-1/PlGF test in clinical practice has the potential to reduce the frequency of adverse pregnancy outcomes for both mother and fetus, and decrease healthcare costs associated with unnecessary hospitalization of women with suspected preeclampsia.

Validation of an Anti-Müllerian Hormone Cutoff for Polycystic Ovarian Morphology in the Diagnosis of Polycystic Ovary Syndrome in the HARMONIA Study: Protocol for a Prospective, Noninterventional Study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women and is diagnosed using the Rotterdam criteria, including diagnosis of polycystic ovarian morphology (PCOM) by transvaginal ultrasound (TVUS). Due to high cost, availability, and the impact of the operator and ultrasound equipment on the reliability of the antral follicle count (AFC) by TVUS, an unmet need exists for a diagnostic test to determine PCOM without TVUS. A strong positive correlation between elevated anti-Müllerian hormone (AMH) levels and AFCs has been demonstrated in women with PCOS. In addition, recent updates to the international evidence-based PCOS guidelines state that serum AMH can be used as an alternative to TVUS-determined AFC, in the diagnosis of PCOM. The retrospective APHRODITE study derived and validated an AMH cutoff of 3.2 ng/mL for the Elecsys AMH Plus or Elecsys AMH assays (Roche) to diagnose PCOM in patients with PCOS. OBJECTIVE: This study aims to further validate, in an independent prospective cohort, the AMH cutoff (3.2 ng/mL) for PCOM determination, which was previously derived and validated in the APHRODITE study. METHODS: This large, prospective, multicenter, population-based, noninterventional study will evaluate the previously established AMH cutoff for the determination of PCOM during the diagnosis of PCOS using the Elecsys AMH Plus immunoassay in an independent population. Participants were women born between July 1985 and December 1987 in Northern Finland; the study partially links to the Northern Finland Birth Cohort 1986. We assessed the enrolled women, determined with the 2023 PCOS Guidelines, for current PCOS status and divided them by phenotype if positive. Each participant had 1 study visit to collect serum samples, record clinical data, and undergo a gynecological examination including TVUS. All data were collected by highly trained midwives or trained gynecologists. Sensitivity, specificity, and agreement measures were used to validate the previously determined cutoff in the whole population and in subpopulations based on phenotype and relevant demographic or clinical factors. The minimum target sample size was approximately 1800 women, including approximately 10% with PCOS. RESULTS: At the time of manuscript submission, participant recruitment had concluded, and 1803 women were enrolled into the study. Data collection is complete and biostatistical analysis is planned for 2023. CONCLUSIONS: To limit variability, there were few TVUS operators and only 2 TVUS machines of the same type. Additionally, all women who were taking oral contraceptives were excluded from the primary analysis population. Selection bias was limited as this was a population-based study and participants were not seeking treatment for PCOS symptoms. Validating the AMH cutoff in a large, population-based study will provide further evidence on the utility of the Elecsys AMH Plus or Elecsys AMH assays in PCOM diagnosis as an alternative to TVUS. Measuring AMH for PCOM diagnosis could reduce delayed or missed diagnoses due to operator-dependent TVUS examinations. TRIAL REGISTRATION: ClinicalTrials.gov NCT05527353; http://tinyurl.com/2f3ffbdz. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48854.

Multicenter evaluation of blood-based biomarkers for the detection of endometriosis and adenomyosis: A prospective non-interventional study.

OBJECTIVE: To evaluate blood-based biomarkers to detect endometriosis and/or adenomyosis across nine European centers (June 2014-April 2018). METHODS: This prospective, non-interventional study assessed the diagnostic accuracy of 54 blood-based biomarker immunoassays in samples from 919 women (aged 18-45 years) with suspicion of endometriosis and/or adenomyosis versus symptomatic controls. Endometriosis was stratified by revised American Society for Reproductive Medicine stage. Symptomatic controls were "pathologic symptomatic controls" or "pathology-free symptomatic controls". The main outcome measure was receiver operating characteristic-area under the curve (ROC-AUC) and Wilcoxon P values corrected for multiple testing (q values). RESULTS: CA-125 performed best in "all endometriosis cases" versus "all symptomatic controls" (AUC 0.645, 95% confidence interval [CI] 0.600-0.690, q < 0.001) and increased (P < 0.001) with disease stage. In "all endometriosis cases" versus "pathology-free symptomatic controls", S100-A12 performed best (AUC 0.692, 95% CI 0.614-0.769, q = 0.001) followed by CA-125 (AUC 0.649, 95% CI 0.569-0.729, q = 0.021). In "adenomyosis only cases" versus "symptomatic controls" or "pathology-free symptomatic controls", respectively, the top-performing biomarkers were sFRP-4 (AUC 0.615, 95% CI 0.551-0.678, q = 0.045) and S100-A12 (AUC 0.701, 95% CI 0.611-0.792, q = 0.004). CONCLUSION: This study concluded that no biomarkers tested could diagnose or rule out endometriosis/adenomyosis with high certainty.

Antimüllerian hormone to determine polycystic ovarian morphology.

OBJECTIVE: To determine a cutoff for the Elecsys AMH Plus immunoassay (Roche Diagnostics International Ltd, Rotkreuz, Switzerland) to identify polycystic ovarian morphology (PCOM), a polycystic ovary syndrome (PCOS) criterion. DESIGN: The AMH Protein in Humans for polycystic ovaRian mOrphology DIagnostic TEsting (APHRODITE) study was a retrospective, multicenter, case-control study. The serum antimüllerian hormone (AMH) level was measured using the Elecsys AMH Plus immunoassay. The antral follicle count was determined using transvaginal ultrasound. An AMH cutoff was derived and validated in separate cohorts with cases of PCOS with full phenotype A (oligo/anovulation, hyperandrogenism, and PCOM) versus that with controls. Exploratory analyses of age and PCOS phenotype were performed. SETTING: Not applicable. PATIENT(S): Polycystic ovary syndrome-positive (PCOS A-D per the Rotterdam criteria) and PCOS-negative women aged 25-45 years. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): A validated cutoff for AMH using the Elecsys AMH Plus assay for PCOM. RESULT(S): In the validation cohort (455 cases and 500 controls), an AMH cutoff of 3.2 ng/mL (23 pmol/L) resulted in a sensitivity of 88.6% (95% confidence interval [CI] 85.3-91.3) and specificity of 84.6% (95% CI 81.1-87.7) for PCOM diagnosis as well as an area under the receiver-operator characteristic curve of 93.6% (95% CI 92.2-95.1). In women aged 25-35 years, the sensitivity and specificity for the cutoff were 88.5% and 80.3%, respectively, versus 77.8% and 90.1%, respectively, in women aged 36-45 years. The results were consistent across PCOS phenotypes A-D. CONCLUSION(S): The Elecsys AMH Plus immunoassay, with a cutoff of 3.2 ng/mL (23 pmol/L), is a robust method for identifying PCOM to aid in PCOS diagnosis.

Short-Term Prediction of Preeclampsia in Chinese Women Using the Soluble fms-Like Tyrosine Kinase 1/Placental Growth Factor Ratio: A Sub-Analysis of the PROGNOSIS Asia Study.

The diagnosis of preeclampsia in China currently relies on limited clinical signs and unspecific laboratory findings. These are inadequate predictors of preeclampsia development, limiting early diagnosis and appropriate management. Previously, the Prediction of Short-Term Outcome in Pregnant Women with Suspected Preeclampsia Study (PROGNOSIS) and PROGNOSIS Asia demonstrated that a soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio of ≤38 can be used to rule out preeclampsia within 1 week, with negative predictive values of 99.3 and 98.6%, respectively. This is an exploratory sub-analysis of the Chinese cohort (n = 225) of the PROGNOSIS Asia study. The primary objectives were to assess the predictive performance of using the sFlt-1/PlGF ratio to rule out preeclampsia within 1 week and to rule in preeclampsia within 4 weeks. The sFlt-1/PlGF ratio was also examined for short-term prediction of fetal adverse outcomes, maternal adverse outcomes, and time to delivery. The overall prevalence of preeclampsia was 17.3%. With the use of an sFlt-1/PlGF ratio of ≤38, the negative predictive value for ruling out preeclampsia within 1 week was 97.3% [95% confidence interval (CI), 93.8-99.1], with a sensitivity of 64.3% and specificity of 85.3%. With the use of an sFlt-1/PlGF ratio of >38, the positive predictive value for ruling in preeclampsia within 4 weeks was 35.0% (95% CI, 20.6-51.7), with a sensitivity of 50.0% and specificity of 86.8%. In the analyses of the sFlt-1/PlGF ratio and fetal adverse outcomes, the area under the receiver operating characteristic curve was 92.8% (95% CI, 83.5-98.7) for ruling out fetal adverse outcomes within 1 week and 79.9% (95% CI, 68.1-90.3) for ruling in fetal adverse outcomes within 4 weeks. An sFlt-1/PlGF ratio of >38 increased the likelihood of imminent delivery 3.3-fold compared with a ratio of ≤38 [hazard ratio, 3.3 (95% CI, 2.1-5.1)]. This sub-analysis confirms the high predictive performance of the sFlt-1/PlGF ratio cutoff of 38 for short-term prediction of preeclampsia in Chinese women, which may help prevent unnecessary hospitalization of women with low risk of developing preeclampsia.

Short-term prediction of preeclampsia using the sFlt-1/PlGF ratio: a subanalysis of pregnant Japanese women from the PROGNOSIS Asia study.

Two prospective multicenter studies demonstrated that a soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio cutoff of ≤38 can rule out preeclampsia within 1 week with a negative predictive value (NPV) of 99.3% (PROGNOSIS) and 98.6% (PROGNOSIS Asia). We report a subanalysis of the Japanese cohort from the PROGNOSIS Asia study. Pregnant women with suspected preeclampsia between gestational weeks 18 + 0 days and 36 + 6 days were enrolled at eight Japanese sites. Primary objectives: Assess the performance of the Elecsys® sFlt-1/PlGF ratio cutoff ≤38 to rule out preeclampsia within 1 week and of the cutoff >38 to rule in preeclampsia within 4 weeks. Key secondary objectives: Prediction of maternal and fetal adverse outcomes (MAOs/FAOs) and their relationship with duration of pregnancy. Of 192 women enrolled, 180 (93.8%)/175 (91.1%) were evaluable for primary/combined endpoint analyses. Overall preeclampsia prevalence was 13.3%. A sFlt-1/PlGF ratio of ≤38 provided an NPV of 100% (95% confidence interval [CI], 97.5-100) for ruling out preeclampsia within 1 week, and a ratio of >38 provided a positive predictive value of 32.4% (95% CI, 18.0-49.8) for ruling in preeclampsia within 4 weeks. The area under the curve for the prediction of preeclampsia/maternal/fetal adverse outcomes within 1 week was 94.2% (95% CI, 89.3-97.8). After adjusting for gestational age and final preeclampsia status, Cox regression indicated a 2.8-fold greater risk of imminent delivery for women with a sFlt-1/PlGF ratio >38 versus ≤38. This subanalysis of Japanese women with suspicion of preeclampsia showed high predictive value for a Elecsys sFlt-1/PlGF ratio cutoff of 38 for short-term prediction of preeclampsia.

Clinical experience with the combined contraceptive vaginal ring in Switzerland, including a subgroup analysis of previous hormonal contraceptive use.

OBJECTIVE: To collect data on cycle and cycle-related symptoms during a second clinical experience programme with the contraceptive vaginal ring (NuvaRing®) in Switzerland. METHODS: Women requiring contraception were recruited by gynaecologists. Questionnaires were used to collect data on cycle and related symptoms, weight, satisfaction and adverse events at baseline and follow-up (typically four cycles). RESULTS: Of the 1053 women included, 36.9% were starters, 22.4% starters anew, and 40.6% switchers. At follow-up, improvement in cycle regularity was significantly better for starters compared with switchers (18.5% versus 11%; p < 0.001). Starters showed the greatest improvement in bleeding duration and severity. Improvement in the severity of premenstrual symptoms (PMS) and dysmenorrhoea was significantly (p  < 0.001) greater in starters compared with switchers (18.5% vs. 9.1% and 26.5% vs. 9.8%, respectively). Menstrual headache improved in all subgroups. Women were satisfied with changes in weight (92%), cycle control (93.6%) and PMS (86%). Adverse events were reported for 17.5% of women and were most frequently ring-related (such as feeling the ring in situ, vaginal discomfort, ring expulsion). CONCLUSIONS: The data support previous findings that the vaginal ring improves cycle-related symptoms (moderate or severe PMS, dysmenorrhoea, and menstrual headache). Not only starters experienced improvements in symptoms; switchers also benefited.

Combining Biomarkers to Predict Pregnancy Complications and Redefine Preeclampsia: The Angiogenic-Placental Syndrome.

Placental dysfunction underlies a spectrum of perinatal pathologies, including preeclampsia and fetal growth restriction. Angiogenesis-related factors, including sFlt-1 (soluble fms-like tyrosine kinase 1) and PlGF (placental growth factor), play an important role in placental dysfunction; altered levels are detectable several weeks before onset of pregnancy complications. In vitro diagnostic tests for these biomarkers can improve early diagnosis and facilitate prediction of maternal and fetal outcomes. We assessed evidence for combining angiogenic biomarkers with other biomarkers or clinical parameters to predict maternal/fetal outcomes in pregnant women with placental dysfunction. Pooled information on placental perfusion (ultrasonography, mean arterial pressure), clinical characteristics, and biomarker levels (PlGF) can improve first-trimester prediction and preeclampsia diagnosis. Angiogenic factors (sFlt-1/PlGF ratio; PlGF alone) with or without clinical characteristics can facilitate second-/third-trimester prediction of early-onset and late-onset preeclampsia. A combination of increased sFlt-1/PlGF ratio and ultrasound can rule out early fetal growth restriction. The sFlt-1/PlGF ratio is also a reliable tool for discriminating between pregnancy-related hypertensive disorders, including superimposed preeclampsia and gestational hypertension. Analysis of angiogenic factors with or without uterine Doppler substantially improves sensitivity and specificity for predicting adverse outcomes and iatrogenic preterm delivery. We propose to extend the American College of Obstetricians and Gynecologists definition of preeclampsia in the future to include the combination of new-onset hypertension and new-onset of altered angiogenic factors (sFlt-1/PlGF ratio or PlGF alone). In summary, altered angiogenic biomarkers indicate placental dysfunction, and their implementation into clinical practice will help reduce the considerable burden of morbidity and mortality associated with adverse pregnancy outcomes as a consequence of angiogenic-placental syndrome.

Diagnostic utility of angiogenic biomarkers in pregnant women with suspected preeclampsia: A health economics review.

Preeclampsia is a major cause of morbidity and mortality, can be difficult to diagnose, and is associated with significant healthcare costs. The prediction, diagnosis and prognosis of preeclampsia have depended on repeated assessment of women with known risk factors, including intensive monitoring and hospitalization. Many of these women may never go on to develop preeclampsia. Recent developments in the pathogenesis of preeclampsia have shown that maternal serum biomarkers can be used to predict preeclampsia. When the ratio of the anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and the pro-angiogenic placental growth factor from the placenta is altered, preeclampsia becomes more likely, providing a diagnostic measurement for risk. The use of angiogenic biomarkers in addition to standard clinical tests can more accurately predict which women are at risk of developing preeclampsia and which are at low or moderate risk, which is likely to streamline the management of pregnant women and target resources in a more efficient way. The studies reviewed here all demonstrate cost savings from use of angiogenic biomarker tests as an addition to standard care.

Evaluation of the Elecsys® anti-Müllerian hormone assay for the prediction of hyper-response to controlled ovarian stimulation with a gonadotrophin-releasing hormone antagonist protocol.

OBJECTIVE: This non-interventional study aimed to validate a pre-specified anti-Müllerian hormone (AMH) cut-off of 15 pmol/L (2.10 ng/mL) for the prediction of hyper-response to controlled ovarian stimulation (COS) using the fully automated Elecsys® AMH immunoassay. STUDY DESIGN: One hundred and forty-nine women aged <44 years with regular menstrual cycles underwent COS with 150 IU/day follicle-stimulating hormone in a gonadotrophin-releasing hormone (GnRH) antagonist protocol. Response to COS (poor vs normal vs hyper-response) was defined by number of oocytes retrieved and occurrence of ovarian hyper-stimulation syndrome (OHSS). RESULTS: Significant differences were seen between response classes for the number of follicles prior to follicle puncture (p < 0.001), the number of retrieved oocytes (p < 0.001) and the occurrence of OHSS (p < 0.001), which were all highest in hyper-responders. The area under the receiver operating characteristic curve for AMH to predict hyper-response was 82.1% (95% confidence interval [CI]: 72.5-91.7). When applying the AMH cut-off of 15.0 pmol/L, a sensitivity of 81.3% (95%CI: 54.4-96.0) to predict hyper-response and a specificity of 64.7% (95%CI: 55.9-72.8) to identify poor/normal responders was reached. CONCLUSION: The Elecsys® AMH assay can reliably predict hyper-response to COS in women undergoing a GnRH antagonist treatment protocol.

Serum Anti-Müllerian Hormone Is Significantly Altered by Downregulation With Daily Gonadotropin-Releasing Hormone Agonist: A Prospective Cohort Study.

Research Question: What is the effect of gonadotropin-releasing hormone (GnRH)-agonist treatment on serum anti-Müllerian hormone (AMH)? Design: This prospective cohort study conducted in a tertiary university hospital comprised patients (n = 52) who self-administered daily triptorelin (0.1 mg/0.1 mL) subcutaneously for 14 days from menstrual cycle day 21 ± 3, between July 2015 and March 2016. Enrolled women were 18-43 years old, considered normal ovarian responders, with a planned GnRH agonist controlled ovarian stimulation protocol. The primary endpoint was to evaluate the effect of GnRH agonist on serum AMH levels after 7 and 14 days of treatment. Results: Under GnRH agonist treatment, serum AMH was significantly decreased vs. baseline on day 7 (mean change from baseline: -0.265 ng/mL; 95% confidence interval [CI], -0.395 to -0.135 ng/mL; p < 0.001). On day 14, serum AMH was significantly increased (mean change from baseline: 0.289 ng/mL; 95% CI, 0.140-0.439 ng/mL; p < 0.001). Although the median change in AMH from baseline was only -14.9% on day 7 and +17.4% on day 14, from day 7 to 14 AMH significantly increased by 0.55 ng/mL (43.8%; p < 0.001), which is of paramount clinical importance. A linear, mixed-effect model demonstrated that GnRH agonist treatment for 7 and 14 days had a highly significant effect on serum AMH concentration after adjustment for confounding factors (age, body mass index, baseline antral follicle count, and visit). AMH assay precision was excellent (four aliquots/sample); coefficient of variation was 1.2-1.4%. Conclusions: GnRH agonist treatment had a clinically significant effect on serum AMH, dependent on treatment duration. The clear V-shaped response of AMH level to daily GnRH agonist treatment has important clinical implications for assessing ovarian reserve and predicting ovarian response, thus AMH measurements under GnRH agonist downregulation should be interpreted with great caution.